Warming up for magnetic resonance imaging

MRI and NMR make use of the quantum-mechanical phenomenon known as nuclear spin; nuclei with odd numbers of protons or neutrons have net magnetic moment and will orient themselves like tiny bar magnets, spin "up" or spin "down," in a strong magnetic field. If the spinning nuclei are knocked off-axis by a jolt of radio-frequency (rf) energy, they wobble or precess at a characteristic rate, a rate that is strongly conditioned by their immediate chemical neighbors. During a certain relaxation time (typical of each atomic species in a specific environment), the nuclei reorient themselves and emit a radio signal that reveals both their position and their chemical surroundings.

The spin-up state requires fractionally less energy, so there's typically a slight excess of spin-up nuclei, about one in a hundred thousand (.001 percent), and it's this tiny difference that yields a useful signal. In clinical settings MRI is usually done using hydrogen nuclei, protons, which are ubiquitous in the human body. But other nuclear species, notably the noble gas xenon, offer advantages over hydrogen that in the case of xenon include a virtual absence of background signal, since there is no xenon in biological systems.

Xenon is particularly useful in MRI and NMR because the spins of its nuclei are readily polarized, in a process involving contact with rubidium vapor irradiated with a laser beam. In such "hyperpolarized" xenon, the excess of spin-up nuclei can be as much as 20 percent, which gives a far stronger signal than hydrogen's .001 percent spin-up excess. Moreover, hyperpolarized xenon has a much longer relaxation time than hydrogen.

Now add the ability to associate a single xenon nucleus with a specific molecular target, for example a protein or sugar on the surface of a cancer cell. To do this, the Pines and Wemmer labs have created biosensors equipped with cages that take up and hold onto xenon atoms; the cages, molecules called cryptophanes, are linked to ligands that target specific molecules of interest. Xenon biosensors engineered with several different ligands can be used at the same time; once in place, biosensors carrying hyperpolarized xenon can localize the MRI signals from a range of different molecules on the target.

The final advance underlying the new technique is called Hyper-CEST: hyperpolarized xenon chemical-exchange saturation transfer. While biosensors can bring the xenon to specific molecular targets, in realistic applications relatively few of these are present, only about one percent compared to the total amount of free xenon injected near that target. The signal from the polarized xenon inside the biosensor cages is consequently much fainter than that from the uncaged polarized xenon nearby.

Team leader Leif Schröder (left) with Monica Smith, who holds a probe housing a phantom target, and Tyler Meldrum, holding a model of a biosensor's cryptophane cage. These members of... Click here for more information.

"About 60 percent of the biosensor cages are filled with xenon," says Schröder, "but the problem is, you get only a tiny, broad NMR signal from the xenon when it is inside the cage. On the other hand, you have thousands of xenon nuclei just sitting around the cage."